Structure-based design and synthesis of lipophilic 2,4-diamino-6- substituted quinazolines and their evaluation as inhibitors of dihydrofolate reductases and potential antitumor agents

Aleem Gangjee, Anup P. Vidwans, Anil Vasudevan, Sherry Queener, Roy L. Kisliuk, Vivian Cody, Ruming Li, Nikolai Galitsky, Joe R. Luft, Walter Pangborn

Research output: Contribution to journalArticle

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Abstract

The synthesis and biological activities of 14 6-substituted 2,4- diaminoquinazolines are reported. These compounds were designed to improve the cell penetration of a previously reported series of 2,4-diamino-6- substituted-pyrido[2,3-d]pyrimidines which had shown significant potency and remarkable selectivity for Toxoplasma gondii dihydrofolate reductase (DHFR), but had much lower inhibitory effects on the growth of T. gondii cells in culture. The target N9-H analogues were obtained via regiospecific reductive amination of the appropriate benzaldehydes with 2,4,6-triaminoquinazoline, which, in turn was synthesized from 2,4-diamino-6-nitroquinazoline. The N9- CH3 analogues were synthesized via a regiospecific reductive methylation of the corresponding N9-H precursors. The compounds were evaluated as inhibitors of DHFR from human, Pneumocystis carinii, T. gondii, rat liver, Lactobacillus casei, and Escherichia coli, and selected analogues were evaluated as inhibitors of the growth of tumor cells in culture. These analogues displayed potent T. gondii DHFR inhibition as well as inhibition of the growth of T: gondii cells in culture. Further, selected analogues were potent inhibitors of the growth of tumor cells in culture in the in vitro screening program of the National Cancer Institute with GI50s in the nanomolar and subnanomolar range. Crystallographic data for the ternary complex of hDHFR-NADPH and 2,4- diamino-6-[N-(2',5'-dimethoxybenzyl)-N-methylamino]-pyrido[2,3-d]pyrimidine, 1c, reveal the first structural details for a reversed N9-C10 folate bridge geometry as well as the first conformational details of a hybrid piritrexim- trimetrexate analogue.

Original languageEnglish
Pages (from-to)3426-3434
Number of pages9
JournalJournal of Medicinal Chemistry
Volume41
Issue number18
DOIs
StatePublished - Aug 27 1998

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Quinazolines
Folic Acid Antagonists
Growth Inhibitors
Tetrahydrofolate Dehydrogenase
Toxoplasma
Cell culture
Antineoplastic Agents
Tumors
Trimetrexate
Cell Culture Techniques
Benzaldehydes
Cells
Amination
Methylation
Bioactivity
NADP
Folic Acid
Liver
Escherichia coli
Rats

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Structure-based design and synthesis of lipophilic 2,4-diamino-6- substituted quinazolines and their evaluation as inhibitors of dihydrofolate reductases and potential antitumor agents. / Gangjee, Aleem; Vidwans, Anup P.; Vasudevan, Anil; Queener, Sherry; Kisliuk, Roy L.; Cody, Vivian; Li, Ruming; Galitsky, Nikolai; Luft, Joe R.; Pangborn, Walter.

In: Journal of Medicinal Chemistry, Vol. 41, No. 18, 27.08.1998, p. 3426-3434.

Research output: Contribution to journalArticle

Gangjee, Aleem ; Vidwans, Anup P. ; Vasudevan, Anil ; Queener, Sherry ; Kisliuk, Roy L. ; Cody, Vivian ; Li, Ruming ; Galitsky, Nikolai ; Luft, Joe R. ; Pangborn, Walter. / Structure-based design and synthesis of lipophilic 2,4-diamino-6- substituted quinazolines and their evaluation as inhibitors of dihydrofolate reductases and potential antitumor agents. In: Journal of Medicinal Chemistry. 1998 ; Vol. 41, No. 18. pp. 3426-3434.
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